Genetic Modifiers of Photoreceptor Development and Maintenance

光感受器发育和维持的基因修饰

• 批准号: 8415902
• 负责人: Neena B Haider
• 金额: $ 39.81万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415902
• 关键词: Affect; Alleles; Bardet-Biedl Syndrome; Biological; Candidate Disease Gene; Cell Cycle; Cells; Chromosome Mapping; Chromosomes, Human, Pair 11; Complete Blindness; Data; Defect; Development; Disease; Electroporation; Gene Expression Profiling; Generations; Genes; Genetic; Genetic Identity; Goals; Health; Hereditary Disease; Human; Individual; Lead; Macular degeneration; Maintenance; Maps; Mitotic; Molecular Profiling; Mus; Mutant Strains Mice; Mutation; Newborn Infant; Nuclear Receptor Gene; Nuclear Receptors; Outcome; Pathology; Pathway interactions; Phenotype; Photoreceptors; Production; Reporting; Retina; Retinal; Retinal Cone; Retinal Defect; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; SW opsin; Severities; Severity of illness; Syndrome; Testing; Transgenic Organisms; Usher Syndrome; cofactor; congenic; disease phenotype; improved; in vivo; mouse model; novel; photoreceptor degeneration; positional cloning; prevent; research study; retinal progenitor cell; retinal rods; treatment strategy

DESCRIPTION (provided by applicant): Retinal degenerations are a group of genetically heterogeneous disorders that can often be classified according to the type of pathology observed in rod and cone photoreceptors. These diseases affect one in every 4000 individuals and it is clear the severity of disease is strongly affected by genetic factors. This large group of disorders includes retinitis pigmentosa, macular degeneration, Bardet-Biedl syndrome, Usher syndrome, and enhanced S-cone syndrome (ESCS), each of which has photoreceptor degeneration as a major component of the disease phenotype. Our long-term goal is to understand the transcriptional networks regulating photoreceptor generation and maintenance, which will enable us to identify novel targets that may be amenable for improved treatment strategies for retinal disease. Our studies and those of others demonstrate that the nuclear receptor Nr2e3 functions in multiple transcriptional networks to regulate the development and maintenance of photoreceptor cells. The PI was the first to report that mutations in human Nr2e3 cause the recessive ESCS, and mutations in mouse Nr2e3 cause excess production of blue opsin expressing cone cells with progressive retinal degeneration. Recent findings also demonstrate that mutations in human Nr2e3 can have significant variability in phenotypic manifestation causing a milder ESCS phenotype, Goldman Favre syndrome, or dominant retinitis pigmentosa. This underscores the importance of Nr2e3-directed transcriptional pathways in retinal disease and suggests the existence of human modifier genes influencing these diseases. The objective of this proposal is to identify genetic modifiers of retinal degeneration in the mouse model Nr2e3rd7/rd7. We utilize two approaches: a genetic mapping strategy, and a candidate gene approach to perform our studies. Aim 1 is to identify the genetic modifier of Nr2e3rd7/rd7, referred to as Mor7, on the AKR/J strain background using a positional cloning approach. We have mapped this modifier gene and developed a congenic line (N9) that ameliorates Nr2e3rd7/rd7 associated retinal degeneration. Aim 2 is to determine whether the nuclear receptor Nr1d1, a cofactor of Nr2e3, can modify Nr2e3rd7/rd7 associated retinal degeneration. We will test our hypothesis by over-expressing Nr1d1 in newborn Nr2e3rd7/rd7 mice to determine if Nr1d1 can rescue retinal degeneration and retinal explant experiments to determine the effects of altered Nr2e3 or Nr1d1 expression on rod or cone photoreceptor cell fate. Our studies will greatly enhance understanding of genetic factors that influence severity of retinal disease, and, provide potentially powerful targets for improved therapies to treat or prevent multiple forms of retinal disease involving photoreceptor degeneration.

描述（由申请人提供）：视网膜变性是一组遗传异质性疾病，通常可以根据在杆状和锥状光感受器中观察到的病理类型进行分类。每4000人中就有1人患有这些疾病，很明显，疾病的严重程度受到遗传因素的强烈影响。这一大类疾病包括色素性视网膜炎、黄斑变性、Bardet-Biedl综合征、Usher综合征和增强型s锥综合征（ESCS），每一种疾病都有光感受器变性作为疾病表型的主要组成部分。我们的长期目标是了解调节光感受器产生和维持的转录网络，这将使我们能够确定新的靶点，从而可以改进视网膜疾病的治疗策略。我们和其他人的研究表明，核受体Nr2e3在多个转录网络中起作用，调节光感受器细胞的发育和维持。PI首次报道了人类Nr2e3突变导致隐性ESCS，小鼠Nr2e3突变导致表达蓝色视蛋白的锥体细胞过量产生并伴有进行性视网膜变性。最近的研究结果还表明，人类Nr2e3的突变在表型表现上具有显著的变异性，可导致较轻的ESCS表型、Goldman Favre综合征或显性色素性视网膜炎。这强调了nr2e3导向的转录途径在视网膜疾病中的重要性，并表明存在影响这些疾病的人类修饰基因。本提案的目的是鉴定小鼠模型Nr2e3rd7/rd7视网膜变性的遗传修饰因子。我们利用两种方法：遗传作图策略和候选基因方法来执行我们的研究。目的1是利用定位克隆方法鉴定AKR/J菌株背景下Nr2e3rd7/rd7的遗传修饰子，简称Mor7。我们已经绘制了这个修饰基因，并开发了一个基因系（N9），改善Nr2e3rd7/rd7相关的视网膜变性。目的2是确定Nr2e3的辅助因子核受体Nr1d1是否可以修饰Nr2e3rd7/rd7相关性视网膜变性。我们将通过在新生Nr2e3rd7/rd7小鼠中过表达Nr1d1来验证我们的假设，以确定Nr1d1是否可以挽救视网膜变性，并通过视网膜移植实验来确定Nr2e3或Nr1d1表达改变对视杆或视锥细胞命运的影响。我们的研究将极大地增强对影响视网膜疾病严重程度的遗传因素的理解，并为改进治疗或预防涉及光感受器变性的多种形式的视网膜疾病提供潜在的强大靶点。